The present invention is directed to a method of blocking N-methyI-D-aspartic (NMDA) acid receptor sites in a mammal in need thereof with an effective NMDA blocking (neuroprotective and antiischemic) amount of 5-(1-hydroxy-2-piperidino)-propyl-2(1H,3H)-indolone analogs, which are defined by the formulas (I), (II) and (III), below, and the pharmaceutically acceptable salts thereof; methods of using these compounds in the treatment of stroke, head trauma, spinal cord trauma, traumatic brain injury, multiinfarct dementia, CNS degenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence and an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.
The excitatory amino acids are an important group of neurotransmitters that mediate excitatory neurotransmission in the central nervous system. Glutamic acid and aspartic acid are two endogenous ligands that activate excitatory amino acid (EAA) receptors. There are two types of EAA receptors, ionotropic and metabotropic, which differ in their mode of signal transduction. There are at least three distinct ionotropic EAA receptors characterized by the selective agonist that activate each type: the NMDA, the AMPA (2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid), and the kainic acid receptors. The ionotropic EAA receptors are linked to ion channels that are permeable to sodium and, in the case of NMDA receptors, calcium. Metabotropic receptors, linked to phosphoinositide-hydrolysis by a membrane associated G-protein, are activated by quisqualic acid, ibotenic acid, and (1S,3R)-1-aminocyclopentane 1,3-dicarboxylic acid.
The NMDA receptor is a macromolecular complex consisting of a number of distinct binding sites that gate an ion channel permeable to sodium and calcium ions. Hansen and Krogsgaard-Larsen, Med. Res. Rev., 10, 55-94 (1990). There are binding sites for glutamic acid, glycine, and polyamines, and a site inside the ion channel where compounds such as phencyclidine (PCP) exert their antagonist effects.
Competitive NMDA antagonists are compounds which block the NMDA receptor by interacting with the glutamate binding site. The ability of a particular compound to competitively bind to the NMDA glutamate receptor may be determined using a radioligand binding assay. See Murphy et al., British J. Pharmacol. 95, 932-938 (1988). The antagonists may be distinguished from the agonists using a rat cortical wedge assay. See Harrison and Simmonds, British J. Pharmacol., 84, 381-391 (1984). Examples of competitive NMDA antagonists include D-2 amino 5-phosphonopentanoic acid (D-AP5), and D-2-amino-7-phosphonoheptanoic acid, Schoepp et al., J. Neur. Transm., 85, 131-143 (1991).
Antagonists of neurotransmission at NMDA receptors are useful therapeutic agents for the treatment of neurological disorders. U.S. Pat. No. 4,902,695 is directed to a series of competitive NMDA antagonists useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease. U.S. Pat. No. 4,968,878 is directed to a second series of competitive NMDA receptor antagonists useful for the treatment of similar neurological disorders and neurodegenerative disorders. U.S. Pat. No. 5,192,751 provides a method of treating urinary incontinence in a mammal which comprises administering an effective amount of a competitive NMDA antagonist.
NMDA antagonists are also useful therapeutic agents with anticonvulsant, anxiolytic, muscle relaxant, and antipsychotic activity, J. Lehmann, The NMDA Receptor, Drugs of the Future 14, No. 11, p. 1059 (1989). NMDA antagonists have also been reported to be effective for treating migraine (Can. J. Neurol. Sci. 19 (4), p. 487, 1992); drug addiction (Science, 251, p. 85, 1991); and neuro-psychiatric disorders related to AIDS (TIPS 11, p. 1 1990).
Ifenprodil is a racemic, so-called di-erythro compound having the relative stereochemical formula ##STR1## which is marketed as a hypotensive agent, a utility shared by a number of close analogs; Carron et al., U.S. Pat. No. 3,509,164; Carron et al., Drug Res., v. 21, pp. 1992-1999 (1971). Ifenprodil has also been shown to possess antiischemic and excitatory aminoacid receptor blocking activity; Gotti et al., J. Pharm. Exp. Therap., v. 247, pp. 1211-21 (1988); Carter et al., Ioc. cid., pp. 1222-32 (1988). See also published European patent application 322,361 and French Patent 2546166. A goal, substantially met by the present invention, has been to find compounds possessing such neuroprotective effect in good measure, while at the same time having lowered or no significant hypotensive effect.
Certain structurally related 1-phenyl-3-(4-aryl-4-acyloxypiperidino)-1-propanolshave also been reported to be useful as analgesics, U.S. Pat. No. 3,294,804; and 1-[4-(amino-andhydroxy-alkyl)phenyl]-2-(4-hydroxy-4-tolylpiperazino)-1-alk anolsandalkanoneshave been reported to possess analgesic, antihypertensive, psychotropic or antiinflammatory activity, Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A).
More recently, in published European Patent Application No. 351,282, compounds which include those of the formula ##STR2## wherein R.sup.a and R.sup.b are each independently hydrogen or (C.sub.1 -C.sub.4)alkyl, R.sup.c is benzyl, phenoxy, benzyloxy or phenoxymethyl, and Z.sup.a is CH.sub.2, C(CH.sub.3).sub.2 or CH.sub.2 CH.sub.2, have been reported as having neuroprotective type activity.
The nomenclature used herein is generally that of Rigaudy et al., IUPAC Nomenclature of Organic Chemistry, 1979 Edition, Pergammon Press, New York. 2(1H,3H)-Indolones are alternatively named as oxindoles.